The BXSB, MRL/1 and MRL/n, and NZB/NZW F1 (B/W) strains have been established in our laboratory. We have studied the sequential development of IgM and IgG antibodies to DNA in the BXSB and MRL/1 mice. Our previous work in B/W mice established the age and sex dependent change in anti-DNA antibodies and the switch from IgM to IgC immunoglobulin class. There is an increased predominance of IgG anti-DNA antibodies in female B/W mice between four and six months of age. This occurs later in male B/W mice but even earlier in male BXSB mice. Male BXSB mice have predominantly IgG antibodies to DNA as early as two months of age which then rises progressively. By contrast, there is very little anti-DNA antibody in female BXSB mice. MRL/1 mice develop a severe autoimmune disease and generalized lymphoproliferation which is not seen in the MRL/n although only a single autosomal recessive gene separates these two substrains. MRL/1 but not MRL/n mice have high levels of predominantly IgG anti-DNA antibodies by four months of age. By contrast, the more normal appearing MRL/n mice have predominantly IgM antibodies to DNA. Thus, in all autoimmune-susceptible strains, there is an early development of predominantly IgG antibodies to DNA in association with an accelerated autoimmune phase of disease. An in vitro spleen cell system to measure synthesis of anti-DNA antibodies has been used in parallel with the studies of serum autoantibodies. In the in vitro system, large amounts of antibodies to DNA are synthesized by spleen cells from female B/W mice, male BXSB mice and female MRL/1 mice. Thus, there is good agreement between the serum levels of anti-DNA antibodies found in vivo in the in vitro synthesis of anti-DNA antibodies by spleen cells.